Patient-derived Granulocyte/Macrophage Colony-Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates
Patient-derived Granulocyte/Macrophage Colony-Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates
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DOI：
10.1164/rccm.201001-0008oc
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发表时间：
2010-07-01
影响因子：
24.7
通讯作者：
Trapnell, Bruce C.
中科院分区：
文献类型：
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作者：
Sakagami, Takuro;Beck, David;Trapnell, Bruce C.
基本原理：粒细胞/巨噬细胞集落刺激因子（GMCSF）自身抗体（GMAb）与特发性肺泡蛋白沉积症（PAP）密切相关，并被认为在其发病机制中起重要作用。然而，GMAb的水平与疾病的严重程度和GMAb也存在于低水平的健康individuals.Objectives：我们的主要目的是要确定人类GMAb是否会重现PAP在健康的灵长类动物。次要目的是确定导致体内GM-CSF信号传导丧失的GMAb浓度（即，临界阈值）。方法：非人灵长（食蟹猴）注射高度纯化的PAP患者来源的GMAb，剂量范围（2.2-50 mg）单次和多次给药研究，以及在阻断抗人免疫球蛋白免疫应答后，在长期给药研究中维持血清水平大于40 μ g/ml长达11个月。GMAb阻断GM-CSF信号传导，导致（1）支气管肺泡灌洗液呈乳白色，表面活性剂脂质和蛋白质增加;（2）肺泡巨噬细胞增大，泡沫状，充满表面活性剂，PU.1和PPAR γ mRNA减少，肿瘤坏死因子-α分泌减少;（3）肺白细胞增多;（4）血清表面活性蛋白-D增加;和（5）中性粒细胞功能受损。GM-CSF信号与GMAb浓度呈负相关，低于5 μ g/ml的临界阈值，这是相似的肺和血液中观察到的值与PAP.Conclusions：GMAb再现PAP在健康灵长类动物的分子，细胞和组织病理学特征，表明GMAb直接导致PAP。这些结果对PAP的治疗有意义，并有助于确定GMAb治疗其他疾病的潜在治疗窗口。
Rationale: Granulocyte/macrophage colony-stimulating factor (GMCSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals.Objectives: Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold).Methods: Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2-50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 mu g/ml for up to 11 months.Measurements and Main Results: GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPAR gamma mRNA, and reduced tumor necrosis factor-a secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 mu g/ml, which was similar in lungs and blood and to the value observed in patients with PAP.Conclusions: GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.